The reinforcing and discriminative stimulus effects of orally administered MDMA

口服 MDMA 的强化和歧视刺激作用

• 批准号: 8067923
• 负责人: Nancy A. Ator
• 金额: $ 36.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067923
• 关键词: Acute; Amphetamines; Area; Behavioral; Clinical; Clinical Treatment; Complement; Data; Development; Dextroamphetamine; Discrimination; Dopamine; Dose; Drug usage; Fruit; Future; Goals; Hallucinogens; Human; Intoxication; Intravenous; Investigation; Laboratories; Laboratory Animals; Mediating; Methodology; Modeling; National Institute of Drug Abuse; Neurotransmitters; Oral; Oranges; Overdose; Papio; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Probability; Procedures; Psychological reinforcement; Psychotropic Drugs; Public Health; Relative (related person); Reporting; Research; Rodent; Route; Self Administration; Self-Administered; Serotonin; Stimulus; Stimulus Generalization; System; Testing; Training; base; drinking; drug discrimination; drug of abuse; ecstasy; experience; improved; insight; neurochemistry; non-drug; nonhuman primate; pre-clinical; reinforcer; research study; response; stimulant abuse

DESCRIPTION (provided by applicant): (1)-3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) is a common drug of abuse that continues to be a public health concern. While the oral route of administration is the most common route used by recreational users, investigations of the reinforcing efficacy and subjective effects of MDMA have rarely used the oral route of MDMA administration. Development of an oral MDMA self-administration model, and a better understanding of how the subjective effects of orally administered MDMA are neurochemically mediated, in a species closely related to humans would significantly enhance our ability to develop pharmacotherapies intended to improve clinical treatment of MDMA abuse. Toward this goal, our first aim is to characterize the relative reinforcing efficacy of orally available MDMA in baboons in two experiments. First, reliable oral self-administration of MDMA will be engendered using a procedure that has been successful in previous studies of psychoactive compounds in baboons. A concentration-response function of orally available MDMA will be compared to vehicle, to d-amphetamine, and to a non-drug oral reinforcer (a fruit drink). In a second experiment, choice procedures will be used to compare multiple concentrations of MDMA to the other reinforcers. These studies will establish the methodology by which reliable, long-term oral MDMA self-administration can be studied experimentally in a nonhuman primate, will determine the range of concentrations across which reinforcement occurs, will determine whether cyclicity in pattern of self-administration develops across days, and will permit comparison to another commonly orally abused stimulant drug, as well as to a preferred non-drug oral reinforcer. Our second aim is to differentiate the discriminative stimulus effects and the neurochemical correlates of a low and a high dose of orally administered MDMA in baboons by use of multiple-dose discrimination procedures. The putatively differential neurochemical changes that occur as a function of lower and higher doses of MDMA administration will be investigated using drug substitution and antagonism testing in baboons trained to discriminate a low or a high dose of MDMA, and then when the baboons are discriminating both doses. We anticipate the discriminative stimulus effects of a low dose of MDMA will differ significantly from those of a high dose of MDMA, as evidenced by the generalization and antagonism profiles for each training dose. These data will be important to our understanding of the extent to which neurochemical mechanisms are mirrored in subjective drug effects in general and for MDMA in particular. The distinguishing features of our proposal are the use of the oral route of MDMA administration under well-controlled laboratory conditions in baboons, and the use of multiple training doses in the investigation of the discriminative stimulus effects of MDMA in baboons. Our proposal will generate data fundamental to the future development of pharmacotherapies for MDMA abuse, thereby contributing to our long-term goal of facilitating treatment of MDMA intoxication, overdose, and use/abuse.

描述（由申请人提供）：(1)-3, 4-亚甲二氧基甲基苯丙胺（MDMA，摇头丸）是一种常见的滥用药物，仍然是一个公共卫生问题。虽然口服给药途径是娱乐使用者最常用的途径，但对 MDMA 的增强功效和主观效果的研究很少使用 MDMA 的口服给药途径。在与人类密切相关的物种中，开发口服 MDMA 自我给药模型，并更好地了解口服 MDMA 的主观效应如何通过神经化学介导，将显着增强我们开发旨在改善 MDMA 滥用临床治疗的药物疗法的能力。为了实现这一目标，我们的第一个目标是通过两个实验来表征狒狒口服 MDMA 的相对增强功效。首先，将采用先前在狒狒身上对精神活性化合物进行的研究中取得成功的程序，实现可靠的口服 MDMA 自我给药。口服 MDMA 的浓度反应函数将与媒介物、d-苯丙胺和非药物口服强化剂（果汁饮料）进行比较。在第二个实验中，将使用选择程序将多种浓度的 MDMA 与其他强化物进行比较。这些研究将建立一种方法，通过该方法可以在非人类灵长类动物中对可靠的长期口服 MDMA 自我给药进行实验研究，将确定发生强化的浓度范围，将确定自我给药模式是否在几天内形成周期性，并将允许与另一种常见的口服滥用兴奋剂药物以及首选的非药物口服强化剂进行比较。我们的第二个目标是通过使用多剂量区分程序来区分低剂量和高剂量口服 MDMA 对狒狒的区分刺激效应和神经化学相关性。假定的神经化学变化随着较低和较高剂量的 MDMA 给药而发生，将通过在狒狒中进行药物替代和拮抗测试来研究，这些狒狒经过训练可以区分低剂量或高剂量的 MDMA，然后当狒狒区分两种剂量时。我们预计低剂量 MDMA 的区别刺激效果将与高剂量 MDMA 的区别刺激效果显着不同，每个训练剂量的泛化和拮抗特征就证明了这一点。这些数据对于我们了解神经化学机制在一般主观药物效应（特别是摇头丸）中反映的程度非常重要。我们提案的显着特点是在控制良好的实验室条件下对狒狒使用 MDMA 口服给药途径，以及在研究 MDMA 对狒狒的辨别刺激作用时使用多种训练剂量。我们的提案将为未来开发 MDMA 滥用药物疗法提供基础数据，从而有助于实现我们促进治疗 MDMA 中毒、用药过量和使用/滥用的长期目标。